Effects of Oxidized Low Density Lipoprotein, Lipid Mediators and Statins on Vascular Cell Interactions
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Christian Weber
Abstract
The integrin heterodimer CD11b/CD18 (αMβ2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2α (8-epi-PGF2α) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear-resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet αllbβ3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac-1-mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro, indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs.
Copyright (c)1999 by Walter de Gruyter GmbH & Co. KG
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Artikel in diesem Heft
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- Frontiers in Molecular Basis of Disease: Inflammatory Diseases
- Mechanisms of Antigen Presentation
- How to Extinguish Lymphocyte Activation, Immunotyrosine-Based Inhibition Motif (ITIM)-Bearing Molecules a Solution?
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- A Potential Role of an Intracellular Signaling Defect in Neutrophil Functional Abnormalities and Promotion of Tissue Damage in Patients with Localized Juvenile Periodontitis
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- Mycophenolic Acid Influences T Helper 2 (Th2) Cytokine Induced Expression of Intercellular Cell Adhesion Molecule -1 (ICAM-1) on Human Endothelial Cells
- Alterations of Endothelial Nucleotide Levels by Mycophenolic Acid Result in Changes of Membrane Glycosylation and E-Selectin Expression
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- A Novel Acute-Phase Marker: Lipopolysaccharide Binding Protein (LBP)
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- Lactoferrin: A Multifunctional Glycoprotein Involved in the Modulation of the Inflammatory Process
- Annexin V and Phospholipid Metabolism
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- Lipoxin and Aspirin-Triggered 15-epi-Lipoxin Cellular Interactions Anti-Inflammatory Lipid Mediators
- Differentiation and Assessment of Cell Death
- Depending on Their Concentration Oxidized Low Density Lipoproteins Stimulate Extracellular Matrix Synthesis or Induce Apoptosis in Human Coronary Artery Smooth Muscle Cells
- Apheresis of Plasma Compounds as a Therapeutic Principle in Severe Sepsis and Multiorgan Dysfunction Syndrome
- Supportive Therapy of the Sepsis Syndrome
- Supplemental Immune Globulins in Sepsis
- Polymorphonuclear Granulocyte Stimulation by Cellulose-Based Hemodialysis Membranes
- Reduction of Circulating Cholesterol and Apolipoprotein Levels during Sepsis
- Outcome Prediction by Traditional and New Markers of Inflammation in Patients with Sepsis
- Isolation of Highly Enriched Human Monocytes from Ten ml Samples of Heparinised Whole Blood
- Endotoxin Adsorbant Based on Immobilized Human Serum Albumin
